Abstract
New promising compounds, derived from the esterification of hyaluronic acid with butyric acid, were investigated in vitro on a non-small cell lung carcinoma cell line (NCI-H460) and an its metastatic subclone (NCI-H460M). All new compounds exerted a dose-dependent inhibitory effect on both cell lines, which expressed CD44, the specific surface receptor for hyaluronic acid, in a very high percentage of cells (90%). HE1, the most effective of these compounds, was 10-fold more effective than sodium butyrate (NaB) in inhibiting cell proliferation. Similarly to NaB, after 24 hours of treatment, HE1 affected the expression of three cell cycle-related proteins (p27kip1, p53 and p21waf1) responsible for growth arrest, indicating that the presence of the hyaluronic acid backbone does not interfere with the biologic activity. Intratumoral treatment with HE1 demonstrated a marked efficacy on primary tumor growth and on lung metastases formation of the murine Lewis Lung Carcinoma model. Altogether, present findings suggest a possible clinical application of these novel butyric pro-drugs in primary and metastatic lung cancer.
Similar content being viewed by others
References
Parker SL, Tong T, Bolden S, Wingo PA: Cancer statistics. CA Cancer J Clin 47: 4–27, 1997
Bains M: Surgical treatment of lung cancer. Chest 100: 826–837, 1991
Coradini D, Biffi A, Costa A, Pellizzaro C, Pirronello E, Di Fronzo G: Effect of sodium butyrate on human breast cancer cell lines. Cell Prolif 30: 149–159, 1997
Yamamoto H, Fujimoto J, Okamoto E, Furuyama J, Tamaoki T, Hashimoto-Tamaoki T: Suppression of growth of hepatocellular carcinoma by sodium butyrate in vitro and in vivo. Int J Cancer 76: 897–902, 1998
Rocchi P, Ferreri AM, Magrini E, Perocco P: Effect of butyrate analogues on proliferation and differentiation in human neuroblastoma cell lines. Anticancer Res 18: 1099–1104, 1998
Coradini D, Pellizzaro C, Marimpietri D, Abolafio G, Daidone M.G: Sodium butyrate modulates cell cycle-related proteins in HT29 human colonica denocarcinoma cells. Cell Prolif 33: 139–146, 2000
Gillewater A, Zou CP, Zhong M, Lotan R: Effects of sodium butyrate on growth, differentiation and apoptosis in head and neck squamous carcinoma cell lines. Head Neck 22: 247–256, 2000
Pellizzaro C, Coradini D, Abolafio G, Daidone MG: Modulation of cell cycle-related proteins but not of p53 expression by sodium butyrate in a human non-small cell lung cancer cell line. Int J Cancer 91: 658–664, 2001
Daniel P, Brazier M, Cerrutti L, Pieri F, Tardivel L, Desmet G, Baillet J, Chany C: Pharmacokinetic study of butyric acid administered in vivo as sodium and arginine butyrate salts. Clin Chim Acta 181: 255–263, 1989
Miller AA, Kurschel E, Osieka R, Schmidt C: Clinical pharmacology of sodium butyrate in patients with acute leukemia. Eur J Cancer Clin Oncol 23: 1283–1287, 1987
Coradini D, Pellizzaro C, Miglierini G, Daidone MG, Perbellini A: Hyaluronic acid as drug delivery for sodium butyrate: Improvement of the anti-proliferative activity on a breast cancer cell line. Int J Cancer 81: 411–416, 1999
Rudki Z, Jothy S: CD44 and the adhesion of neoplastic cells. J Clin Pathol: Mol Pathol 50: 57–71, 1997
Naor D, Nedvetzki S, Golan I, Melnik L, Faitelson Y: CD44 in cancer. Crit Rev Clin Lab Sci 39: 527–579, 2002
Ariza A, Mate JL, Isamat M, Lopez D, Von Uexkull-Guldeband C, Rosell R, Fernandez-Vasalo A, Navas-Palacios JJ: Standard and variant CD44 isoforms are commonly expressed in lung cancer of the non-small cell type but not of the small cell type. J Pathol 177: 363–368, 1995
Miyoshi T, Kondo K, Hino N, Uyama T, Monden Y: The expression of the CD44 variant exon 6 is associated with lymph node metastasis in non-small cell lung cancer. Clin Cancer Res 3: 1289–1293, 1997
Geran RL, Greenberg NH, MacDonald MM, Schumacher AM, Abbott BJ. Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemother Rep 3: 13, 1972
Naor D, Sionov RV, Ish-Shalom D: CD44: structure, function, and association with the malignant process. In: Advances in Cancer Research. Academic Press 1997, pp 241–319
Skubitz AP. Adhesion molecules. Cancer Treat Res 107: 305–329, 2002
Alaniz L, Cabrera PV, Blanco G, Ernst G, Rimoldi G, Alvarez E, Hajos SE. Interaction of CD44 with different forms of hyaluronic acid. Its role in adhesion and migration of tumor cells. Cell Commun Adhes 9: 117–130, 2002
Rossin R, Zorzet S, Zanella A, Turrrin C, Sava G, Moschini G, Perbellini A, Mazzi U. In vivo biodistribution studies on hyaluronanbutyrate by means of 99mTc direct labelling and YAP camera. In: M. Nicolini and U. Mazzi (eds), Technetium, rhenium and other metals in chemistry and nuclear medicine. SG Editoriali, Padova, Italy, 2002, pp. 689–693.
Luo Y, Prestwich GD: Cancer-targeted polymeric drugs. Curr Cancer Drug Targets 2: 209–226, 2002.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Coradini, D., Pellizzaro, C., Abolafio, G. et al. Hyaluronic-acid butyric esters as promising antineoplastic agents in human lung carcinoma: A preclinical study. Invest New Drugs 22, 207–217 (2004). https://doi.org/10.1023/B:DRUG.0000026247.72656.8a
Issue Date:
DOI: https://doi.org/10.1023/B:DRUG.0000026247.72656.8a